Metastasis is a major cause of mortality in patients with cancer. Identifying molecules that promote tumor metastasis will further elucidate mechanisms underlying the complex metastatic process. Moreover, such molecules can serve as biomarkers to predict the metastatic potential of tumors which is essential for improving prognosis, treatment strategies, and providing targets for cancer therapy. Despite the numerous biomarkers reported, few are useful for predicting metastasis. In our recent studies, we have uncovered a novel splice isoform of the prohormone processing enzyme, carboxypeptidase E (CPE-deltaN) that is elevated in metastatic hepatocellular, colon, breast, prostate, head and neck carcinoma cells. CPE-deltaN lacks the N-terminus present in secretory granule wild-type CPE, and is localized to the nucleus of metastatic cancer cells. Overexpression of CPE-deltaN in hepatocellular carcinoma (HCC) cells promoted their proliferation and migration by up-regulating expression of a metastasis gene. SiRNA knockdown of CPE-deltaN expression in highly metastatic HCC cells inhibited their growth and metastasis in nude mice. In clinical studies, CPE-deltaN RNA quantification in primary HCC and colon tumors from patients established a level, above which predicted metastasis with high prognostic significance (p<0.0001). Thus, CPE-deltaN is a new mediator of tumor metastasis and a powerful prognostic marker.